Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

Fournier, Clémence; Barbier, Mathieu; Camuzat, Agnès; Anquetil, Vincent; Lattante, Serena; Clot, Fabienne; Cazeneuve, Cécile; Sabatelli, Mario; Forlani, Sylvie; Jornéa, Ludmila; LeGuern, Eric; Brice, Alexis; Auriacombe, Sophie; Belliard, Serge; Blanc‬, ‪Frederic; Bouteleau-Bretonnière, Claire; Ceccaldi, Mathieu; Didic, Mira; Duyckaerts, Charles; Etcharry-Bouix, Frédérique; Golfier, Véronique; Lacomblez, Lucette; Michel, Bernard‐François; Thomas‐Antérion, Catherine; Pariente, Jérémie; Sellal, François; Vercelletto, Martine; Benchetrit, Eve; Bertín, Hugo Darío; Bertrand, Anne; Bissery, Anne; Bombois, Stéphanie; Boncœur, Marie-Paule; Cassagnaud, Pascaline; Chastan, Mathieu; Chen, Yaohua; Chupin, Marie; Colliot, Olivier; Couratier, Philippe; Delbeucq, Xavier; Deramecourt, Vincent; Delmaire, Christine; Gérardin, Emmanuel; Hossein-Foucher, Claude; Dubois, Bruno; Habert, Marie‐Odile; Hannequin, Didier; Lautrette, Géraldine; Lebouvier, Thibaud; Ber, Isabelle Le; Lehericy, Stéphane; Toullec, Benjamin Le; Lévy, Richard; Martineau, Kelly; Mackowiak, Marie-Anne; Monteil, Jacques; Pasquier, Florence; Petyt, G.; Pradat, Pierre‐François; Oya, Assi-Hervé; Rinaldi, Daisy; Rollin‐Sillaire, Adeline; Salachas, François; Sayah, Sabrina; Wallon, David

doi:10.1016/j.neurobiolaging.2018.09.010

Cited by 40 publications

(54 citation statements)

References 18 publications

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“…Although these studies could indeed point to anticipation, our work suggests that this may not be the case. In successive generations, we actually noticed that the repeat expansion had a tendency to contract, which was also reported by others [12]. One wonders, therefore, whether the earlier age at onset reported in the former study might be a reflection of selection bias, recall bias, and/or diagnostic bias.…”

Section: Discussionsupporting

confidence: 86%

“…Information is provided regarding the onset age (OA), death age (DA), expansion size (S), methylation level (M), and expression level (E), when available (N/A) repeat length, and hence, the length in blood at a given point in time may be a poor reflection of the original length. As such, this could explain conflicting results reported in the literature, depending on the time-points or tissues analyzed as well as the number of unaffected individuals studied [11,12,14,17].…”

Section: Discussionmentioning

confidence: 97%

“…Although methylation of the C9orf72 promoter, expression levels of C9orf72 transcripts, and the length of the hexanucleotide expansion have been studied in blood [7][8][9][10][11][12][13][14][15][16][17][18], they have not been evaluated together in a single comprehensive large-scale study. Hence, we set out to perform a thorough characterization of our clinical cohort, which enabled us to examine correlations between these variables and to determine whether they are associated with features of C9orf72-linked diseases.…”

Section: Introductionmentioning

confidence: 99%

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Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Jackson

Finch

Baker

et al. 2020

Mol Neurodegeneration

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Background: A repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) is the most common genetic cause of two debilitating neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Currently, much remains unknown about which variables may modify these diseases. We sought to investigate associations between C9orf72 promoter methylation, RNA expression levels, and repeat length, their potential effects on disease features, as well as changes over time and within families.Methods: All samples were obtained through the ALS Center at Mayo Clinic Florida. Our primary cohort included 75 unrelated patients with an expanded C9orf72 repeat, 33 patients who did not possess this expansion, and 20 control subjects without neurodegenerative diseases. Additionally, 67 members from 17 independent C9orf72 families were selected of whom 33 harbored this expansion. Longitudinally collected samples were available for 35 C9orf72 expansion carriers. To increase our understanding of C9orf72-related diseases, we performed quantitative methylation-sensitive restriction enzyme-based assays, digital molecular barcoding, quantitative real-time PCR, and Southern blotting.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Jackson

Finch

Baker

et al. 2020

Mol Neurodegeneration

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“…Not surprisingly therefore, the asymmetry of the replication fork leads to orientation-dependent repeat instability. Indeed, CAG/CTG repeats tend to contract if the CTG tract is in the lagging strand template and tend to expand if the CAG tract is in the lagging strand template in bacterial (35,283), yeast (161,162,284,285), and mammalian cells (206,280,286). Typically, this orientation dependence is explained by the fact that an imperfect hairpin formed by a (CTG) n tract is more stable than the one formed by a (CAG) n tract.…”

Section: Evidence That Replication Promotes Repeat Instabilitymentioning

confidence: 99%

“…Diseases with strong correlations between the number of repeats and age of onset are SCA7 (16,17), SCA3 (18), SCA2 (19 -21), SCA37 (22), HD (23)(24)(25)(26), DM1 (27,28), dentatorubral-pallidoluysian atrophy (DRPLA) (29,30), X-linked dystonia parkinsonism (XDP) (31), familial adult myoclonic epilepsy 3 (FAME3) (32), and Friedreich's ataxia (FRDA) (33,34). For some disorders, the correlation between the number of repeats and symptom manifestation is less clear, although there typically is a marginally significant trend (35)(36)(37)(38)(39). Second, expansion of one disease-causing repeat does not promote expansions of other repeats in the patient's genome.…”

mentioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Evidence‐based consensus guidelines for ALS genetic testing and counseling

Roggenbuck,

Eubank,

Wright

et al. 2023

Ann Clin Transl Neurol

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ObjectiveAdvances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet “standard of care.” Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.MethodsCore clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA‐P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.ResultsA total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single‐step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.InterpretationThese evidence‐based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.

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Relations between C9orf72 expansion size in blood, age at onset, age at collection and transmission across generations in patients and presymptomatic carriers

Cited by 40 publications

References 18 publications

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Evidence‐based consensus guidelines for ALS genetic testing and counseling

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